A major cause of brain damage in the perinatal period is hypoxic-ischemic (H-I) injury. This type of injury often leads to static encephalopathy with permanent motor deficits (cerebral palsy) as well as mental impairment and seizures. There is currently no treatment for this significant clinical problem. Recent data indicate that endogenous neurotrophic factors, specifically the neurotrophins (NTs) may play a role in H-I injury. Recent work also suggests that NTs may be particularly important to the developing brain where NT actions are much more robust than in the adult and where the mode of cell death following H-I and other insults appears to favor apoptosis. Recently, we have found that certain NTs, probably acting through both direct and indirect mechanisms, appear to he markedly protective to the neonatal rat brain in a model of H-I injury. In this proposal, we will test the hypothesis that NTs are protective against neonatal H-I induced neuronal death and cognitive changes when given before or after an insult. A-corollary to this hypothesis is that alterations in NT signaling or its downstream mediators will impact on neuronal death and alter outcome in neonatal H-I injury. In specific aim l, we will characterize the activity of endogenous and exogenous NTs and their receptors during brain development and following both hypoxia and hypoxia-ischemia in vivo. In aim 2, we determine the extent and timecourse of apoptotic cellular changes following a neonatal H-I insult. In aim 3, we will determine whether NGF, BDNF and NT-3 protect against brain injury in vivo if given either before or after H-I induced injury. In aim 4, we will determine if the absence of the NT receptor trkB will worsen H-I injury and whether absence of the pro-apoptotic gene bax will prevent H-I induced injury. In aim 5, we will determine whether H-I injury in neonatal rats results in alterations in spatial memory and whether NTs can prevent these changes. These studies should provide new insights into differences between the response of the neonatal and adult brain to hypoxia-ischemia and better define the role of NTs and their receptors in this process. They will also further define the potential of NTs as treatments for neonatal H-I brain injury.